Autoantigen-Induced Focusing of Vβ13+ T Cells Precedes Onset of Autoimmune Diabetes in the LEW.1WR1 Rat

  1. Elizabeth P. Blankenhorn1
  1. 1Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, PA
  2. 2Division of Endocrinology & Metabolism, Department of Medicine, University of Massachusetts Medical School, Worcester, MA
  1. Corresponding author: Elizabeth P. Blankenhorn, libby{at}drexelmed.edu.

Abstract

The earliest events leading to autoimmune type 1 diabetes (T1D) are not known in any species. A T-cell receptor (TCR)-variable region, TCR-Vβ13, is required for susceptibility to autoimmune diabetes in rats, and selective depletion of Vβ13+ T cells with an allele-specific monoclonal antibody prevents disease in multiple rat strains. To investigate the role of Vβ13 early in diabetes, we examined islet T-cell transcripts in susceptible (LEW.1WR1) and resistant (LEW.1W and Wistar Furth) strains induced with polyinosinic:polycytidylic acid. Vβ13+ T cells displayed antigenic focusing in LEW.1WR1 islets 5 days postinduction and were characterized by a substantial decrease in complementarity determining region 3 diversity. This occurred prior to significant islet T-cell accumulation (day 7) or frank diabetes (days 10–14). Vβ13+ transcripts increased in LEW.1WR1 islets during diabetes progression, but not in resistant rats. We also analyzed transcript clonality of rat TCR-Vα5, an ortholog of the dominant TCR-Vα chain found on insulin B:9-23–reactive T cells in nonobese diabetic rat islets. We observed clonal expansion of Vα5+ transcripts in prediabetic LEW.1WR1 islets, suggesting that rat Vα5 is also an important component of islet autoantigen recognition. These data provide additional evidence that genome-encoded TCR sequences are important determinants of genetic susceptibility to T1D.

Footnotes

  • Received March 20, 2013.
  • Accepted October 17, 2013.

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  1. Diabetes vol. 63 no. 2 596-604
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